Atlas of the plasma proteome in health and disease in 53,026 adults

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Large-scale proteomics studies can refine our understanding of health and disease enable precision medicine. Here, we provide a detailed atlas 2,920 plasma proteins linking to diseases (406 prevalent 660 incident) 986 health-related traits in 53,026 individuals (median follow-up: 14.8 years) from the UK Biobank, representing most comprehensive proteome profiles date. This revealed 168,100 protein-disease associations 554,488 protein-trait associations. Over 650 were shared among at least 50 diseases, over 1,000 showed sex age heterogeneity. Furthermore, demonstrated promising potential discrimination (area under curve [AUC] > 0.80 183 diseases). Finally, integrating protein quantitative trait locus data determined 474 causal proteins, providing 37 drug-repurposing opportunities 26 targets with favorable safety profiles. These results an open-access proteome-phenome resource (https://proteome-phenome-atlas.com/) help elucidate biological mechanisms accelerate development biomarkers, prediction models, therapeutic targets.

Language: Английский

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Current and novel biomarkers in cardiogenic shock

European Journal of Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract Cardiogenic shock (CS) carries a 30–50% in‐hospital mortality rate, with little improvement in outcomes the last decade. Challenges improving are closely linked to frequent late presentation or diagnosis of CS where ‘point no return’ has often passed, leading haemodynamic dysregulation, progressive myocardial depression, hypotension, and downward spiral hypoperfusion, organ dysfunction decreasing function, driven by inflammation metabolic derangements. Novel therapeutic interventions may have varying efficacy depending on type stage which they applied. Biomarkers that aid prediction early detection CS, provide signs define prognosis could help optimize management. Temporal change such biomarkers, particularly response pharmacological and/or mechanical circulatory support, can guide management predict outcome. Several novel biomarkers enhance compared conventional parameters as lactate, some, adrenomedullin circulating dipeptidyl peptidase 3, also able development CS. Some reflect systemic (e.g. interleukin‐6, angiopoietin 2, fibroblast growth factor 23 suppressor tumorigenicity 2) not specific yet inform activation important pathways involved spiral. Other signal end‐organ hypoperfusion targeted interventions, while some serve targets. We critically review current prediction, detection, prognostication Future use improve these high‐risk patients.

Language: Английский

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Inflammatory Mediators of Endothelial Dysfunction

Life, Journal Year: 2023, Volume and Issue: 13(6), P. 1420 - 1420

Published: June 20, 2023

Endothelial dysfunction (ED) is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), inflammatory factors, as well deficiency of nitric oxide (NO) bioavailability. It has been reported that the maintenance endothelial cell integrity serves a significant role in human health disease due to involvement endothelium several processes, such regulation vascular tone, hemostasis thrombosis, adhesion, smooth muscle proliferation, inflammation. Inflammatory modulators/biomarkers, IL-1α, IL-1β, IL-6, IL-12, IL-15, IL-18, tumor necrosis factor α, or alternative anti-inflammatory cytokine IL-10, adhesion molecules (ICAM-1, VCAM-1), involved atherosclerosis progression have shown predict cardiovascular diseases. Furthermore, signaling pathways, NLRP3 inflammasome, are associated with response disrupted H2S bioavailability postulated be new indicators for inflammation its dysfunction. In this review, we summarize knowledge plethora reviews, research articles, clinical trials concerning key modulators pathways

Language: Английский

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Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1167 - 1167

Published: May 24, 2024

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. complex has multifaceted central role both normal physiological also pathological responses. uPAR expressed glycophosphatidylinositol (GPI)-linked interacting with vitronectin, integrins, G protein-coupled receptors, growth factor receptors within large lipid raft. Through protein-to-protein interactions, cell surface modulates intracellular signaling, altering cellular adhesion migration. modifies extracellular activity, activating to form plasmin, which breaks down fibrin, dissolving clots matrix metalloproteinases that lyse connective tissue, allowing immune cancer invasion releasing factors. biomarker for inflammatory diseases cancer; soluble fragments (suPAR) are increased viral sepsis (COVID-19), bowel disease, metastasis. Here, we provide comprehensive overview the structure, function, current examining suPAR diagnostic markers therapeutic targets. Understanding developing ongoing development antibody, small-molecule, nanogel, virus-derived immune-modulating treatments target uPAR.

Language: Английский

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Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study

JOR Spine, Journal Year: 2024, Volume and Issue: 7(2)

Published: June 1, 2024

Abstract Background Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations 91 CIPs cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), canal stenosis (SCS), spondylolisthesis/spondylolysis. Methods Genetic variants data for SDDs were obtained from genome‐wide association studies (GWAS) database. We inverse variance weighted (IVW) as primary method, analyzing validity robustness of results through pleiotropy heterogeneity tests performing reverse MR analysis test causality. Results The IVW with Bonferroni correction indicated that beta‐nerve growth factor (β‐NGF), C‐X‐C motif chemokine 6 (CXCL6), interleukin‐6 (IL‐6) can increase risk CS. Fibroblast 19 (FGF19), sulfotransferase 1A1 (SULT1A1), tumor necrosis factor‐beta (TNF‐β) PD/SD risk, whereas urokinase‐type plasminogen activator (u‐PA) decrease PD/SD. FGF19 TNF SCS risk. STAM binding protein (STAMBP) T‐cell surface glycoprotein CD6 isoform (CD6 isoform) spondylolisthesis/spondylolysis, monocyte chemoattractant 2 (MCP2) latency‐associated peptide transforming beta 1 (LAP‐TGF‐β1) spondylolisthesis/spondylolysis Conclusions multiple genetically predicted four (CS, PD/SD, SCS, spondylolisthesis/spondylolysis). provides reliable genetic evidence in‐depth exploration involvement in pathogenic mechanism novel potential targets SDDs.

Language: Английский

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Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue

Journal of Allergy and Clinical Immunology, Journal Year: 2024, Volume and Issue: 154(4), P. 952 - 964

Published: May 24, 2024

Language: Английский

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Activation of the Coagulation Cascade as a Universal Danger Sign

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(2), P. 108 - 108

Published: Feb. 9, 2025

Hemostasis is a mechanism that stops bleeding from an injured vessel, involves multiple interlinked steps, culminating in the formation of “clot” sealing damaged area. Moreover, it has long been recognized inflammation also provokes activation coagulation system. However, there increasing amount evidence revealing immune function hemostasis This review collects and analyzes results experimental studies data clinical observations confirming inflammatory hemostasis. Here, we summarize latest knowledge pathways system under influence factors. The analyzed allow us to consider components as receptors recognizing «foreign» or «self» or/and damage signals initiate reinforce affect direction adaptive response. To sum up, findings collected classify factors, such Damage-Associated Molecular Patterns break down conventional concepts

Language: Английский

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Endothelial Homeostasis Under the Influence of Alcohol—Relevance to Atherosclerotic Cardiovascular Disease

Nutrients, Journal Year: 2025, Volume and Issue: 17(5), P. 802 - 802

Published: Feb. 26, 2025

Alcohol, in the form of ethyl alcohol or ethanol, is a widely consumed substance with significant implications for human health. Research studies indicate multifaceted effects on cardiovascular system both protective and harmful atherosclerotic disease (ASCVD), depending amount involved pattern consumption. Among critical components are endothelial cells which line blood vessels. These pivotal maintaining vessel homeostasis, regulating flow, preventing thrombosis. Their compromised function correlates arterial progression predictive events. Here we review research investigating how exposure affects endothelium to gain insight into potential mechanisms mediating alcohol's influence ASCVD underlying heart attacks strokes. Studies highlight opposite low versus high levels many functions. In general, low-to-moderate (~5-25 mM) maintain non-activated state supporting vascular while higher (≥50 lead dysfunction promotes atherosclerosis. biphasic might underlie varying impacts different consumption patterns ASCVD.

Language: Английский

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Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults

Journal of the American Heart Association, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Background Calcific aortic valve disease (CAVD), and ensuing severe stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding molecular underpinnings calcification (AVC) necessary to develop pharmacologic interventions. Methods Results We undertook large‐scale plasma proteomics in a cohort study adults ≥65 years old, CHS (Cardiovascular Health Study), identify individual proteins associated with echocardiographic AVC incident moderate/severe AS. Proteomics measurements were performed aptamer‐based SomaLogic platform ~5000 proteins. Significant validated second cohort, AGES‐RS (Age, Gene/Environment Susceptibility‐Reykjavik which assessed AS by computed tomography. The potential causal associations replicated tested 2‐sample Mendelian randomization using identified cis protein quantitative trait loci consortia having tomography‐quantified or as outcomes. Six showed Bonferroni‐corrected significant relationships CHS. Three these, CXCL‐12 (C‐X‐C chemokine ligand 12), KLKB1 (kallikrein), leptin, AGES‐RS, former 2 novel. Only 1 protein, CXCL6, near‐significant association replication was significantly (positively) analysis conducted for KLKB1, CXCL12, supported relationship higher lower (beta=−0.25, P =0.009). Conclusions This older newly largely 3 circulating calcific disease, may have basis. Additional investigation determine if could be harnessed therapeutics.

Language: Английский

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Extensive Review of Nanomedicine Strategies Targeting the Tumor Microenvironment in PDAC

International Journal of Nanomedicine, Journal Year: 2025, Volume and Issue: Volume 20, P. 3379 - 3406

Published: March 1, 2025

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in world, mainly because its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote progression metastasis. In addition, extracellular leads to vascular collapse, increased interstitial fluid pressure, obstruction lymphatic return, thereby hindering effective drug delivery, deep penetration, immune cell infiltration. Therefore, reshaping TME enhance perfusion, increase reverse suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, chemotherapy, face significant limitations. Surgery challenging due location growth, while chemotherapy radiation are hindered by dense TME. recent years, advancement nanotechnology provided new opportunities improve efficacy. Nanoscale delivery systems (NDDSs) provide several advantages, improved stability vivo, enhanced reduced systemic toxicity. However, clinical translation PDAC therapy faces challenges. These include need precise targeting control over release, potential responses nanocarriers, scalability cost-effectiveness production. This article provides an overview latest nanobased methods achieving better outcomes overcoming resistance. We pay special attention TME-targeted context discuss advantages limitations current strategies, emphasize promising developments. By emphasizing enormous NDDSs improving treatment patients with critically discussing traditional challenges faced breakthroughs, our review paves way future research this rapidly developing field.

Language: Английский

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